Background: Ulceration has long been recognized as an indicator of poor prognosis in melanoma. Multiple morphologic characteristics have been proposed as predictors of ulceration; however, thickness is a persistent confounder in previous studies. In the following study, we matched ulcerated melanomas and non-ulcerated melanomas by Breslow thickness to determine whether any previously described morphologic features provide insight into ulceration. Additionally, we performed extracellular matrix gene expression array analysis in order to describe the extracellular conditions that promote ulceration.Design: Cases of ulcerated melanomas were selected from a prospective cohort of patients diagnosed with melanoma between 1990 and 2000 in central Texas with a median follow up of 130 months. They were matched by Breslow thickness to non-ulcerated melanomas from the same cohort. Where possible, they were also matched by tumor location and age. Slides were reviewed and evaluated for mitotic rate, vascularity, tumor infiltrating lymphocytes (TIL), regression, solar elastosis, and necrosis. In a subset of recently diagnosed non-ulcerated and ulcerated melanoma, cDNA was extracted from micro-dissected tissue and analyzed with the RT^2 Profiler PCR ARRAY (Rotor-Gene Format) Human EMT kit. Univariate and multivariate statistical analysis was performed using SAS 9.1 and SPSS 20.Results: Of 401 patients diagnosed with melanoma between 1990 and 2000, 9.7% (39) were ulcerated. In this cohort both ulceration and Breslow thickness were found to be the strongest independent histologic predictors of disease free survival and overall survival (p<0.05 by Cox PH). 54 cases were reviewed, 34 with ulcerated and 20 with non-ulcerated melanoma with 14 matched pairs. None of the morphologic features mentioned were found to be associated with ulceration, including mitotic rate and vascularity (p>0.10 by Chi square and McNemar's test for matched pairs). The PCR gene expression array showed ulceration to be associated with an upregulation in MMP3 and with a downregulation in CTNNB1.Conclusions: In this matched pair, nested case control study, no morphologic characteristics other than thickness were consistently associated with ulceration. While ulceration is associated with thickness and, by extension, mitotic rate, this fails to explain why some thin melanomas ulcerate and have a poor prognosis while some thick melanomas fail to ulcerate. Results from our gene expression array suggest ulceration is the end result of persistent disruption of adherens junction proteins (CTNNB1) and increased breakdown of extracellular matrix proteins (MMP3).Category: Dermatopathology